Neutrophil elastase activity following cathepsin C (CatC, or DPP1) inhibition with BI 1291583 in people with bronchiectasis

<bold>Background</bold> Neutrophil elastase (NE) is activated by CatC, and increased airway NE activity is linked to poor outcomes in people with bronchiectasis (BE). We report the effects of the CatC inhibitor BI 1291583 on NE activity in people with BE in the AIRLEAF^® study. <bold>Methods</bold> AIRLEAF^® enrolled 322 adults with BE, examining once-daily BI 1291583 administration (1/2.5/5 mg doses) vs placebo up to 48 weeks. Participants had a history of pulmonary exacerbations (PExs) requiring antibiotic treatment in the year prior to screening (≥2 PExs or 1 PEx with St. George’s Respiratory Questionnaire [SGRQ] Symptoms score >40). Free sputum NE activity was measured at baseline and over time, using a fluorescent substrate-based enzymatic activity assay. Descriptive statistics for absolute NE activity over time were calculated; change from baseline in sputum NE activity and corresponding NE inhibition were estimated using a mixed model with repeated measures. <bold>Results</bold> At baseline, mean sputum NE activity was similar across all treatment groups, with no differences in participants who had ≥2 PExs or 1 PEx with SGRQ Symptoms score >40. Higher baseline NE activity (p<0.01) was observed in those positive for <italic>P. aeruginosa</italic> and those from East Asia. At Weeks 12 and 24, placebo-corrected-mean-adjusted NE inhibition was 24.1% and 44.9%, 78.4% and 78.9%, and 80.2% and 90.8% in the BI 1291583 1 mg, 2.5 mg, and 5 mg groups, respectively. <bold>Conclusions</bold> Dose-dependent NE inhibition was seen with BI 1291583. However, the 2.5 mg dose achieved the greatest clinical efficacy in AIRLEAF^®;¹ several mechanisms may be responsible for this. ¹Chalmers JD, <italic>et al.</italic> Eur Respir J 2025;65:2401551